In recent years, diseases such as diabetes, hypertension, dyslipidemia and obesity which can be a risk factor for arteriosclerotic diseases have been rapidly increasing due to changes in life style with improvements in living standard, i.e., high calorie and high cholesterol type diet, obesity, lack of exercise, aging, and the like. It is known that, although being a risk factor independent of each other, overlap of the diseases can cause an occurrence of arteriosclerotic diseases at higher frequency or aggravation of the diseases. As such, with the understanding of a condition having a plurality of risk factors for arteriosclerotic diseases as metabolic syndrome, efforts have been made to elucidate the cause of the syndrome and to develop a therapeutic method therefor.
Angiotensin II (herein below, also abbreviated as “AII”) is a peptide that is found to be an intrinsic pressor substance produced by renin-angiotensin system (i.e., RA system). It is believed that pharmacological inhibition of angiotensin II activity can lead to treatment or prevention of circulatory diseases such as hypertension. Accordingly, an inhibitor for angiotensin converting enzyme (ACE) which inhibits the enzyme for promoting the conversion of angiotensin I (AI) to angiotensin II has been clinically used as an inhibitory agent for RA system. Furthermore, an orally administrable AII receptor blocker (Angiotensin Receptor Blocker: ARB) has been developed, and losartan, candesartan, telmisartan, valsartan, olmesartan, irbesartan, and the like are already clinically used as a hypotensive agent. It is reported by many clinical or basic studies that, as having not only a hypotensive activity but also other various activities including an anti-inflammatory activity, an endothelial function improving activity, a cardiovascular remodeling inhibiting activity, an oxidation stress inhibiting activity, a proliferation factor inhibiting activity, insulin resistance improving activity, and the like, ARB is useful for cardiovascular diseases, renal diseases, arteriosclerosis, and the like (Non-Patent Documents 1 and 2). Most recently, it is also reported that ARB particularly has a kidney protecting activity which does not depend on a hypotensive activity (Non-Patent Document 3).
Meanwhile, three isoforms, i.e., α, γ and δ have been identified so far for peroxisome proliferator-activated receptors (PPARs) which belong to a nuclear receptor superfamily. Among them, PPARγ is an isoform most abundantly expressed in an adipose tissue and it plays an important role in differentiation of adipocytes or metabolism of glycolipids. Currently, thiazolidinedione derivatives (i.e., TZD) such as pioglitazone or rosiglitazone are clinically used as a therapeutic agent for diabetes having a PPARγ activation effect, and they are known to have an activity of improving insulin resistance, glucose tolerance, lipid metabolism, and the like. Further, it is recently reported that, based on activation of PPARγ, TZD exhibits various activities including a hypotensive activity, an anti-inflammatory activity, an endothelial function improving activity, a proliferation factor inhibiting activity, an activity of interfering RA system, and the like. It is also reported that, according to such multiple activities, TZD shows a kidney protecting activity particularly in diabetic nephropathy without depending on blood sugar control (Non-Patent Documents 4, 5, 6, 7, and 8). Meanwhile, there is also a concern regarding adverse effects of TZD caused by PPARγ activation, such as body fluid accumulation, body weight gain, peripheral edema, and pulmonary edema (Non-Patent Documents 9 and 10).
It has been recently reported that telmisartan has a PPARγ activation effect (Non-Patent Document 11). It has been also reported that the irbesartan has the same activity (Non-Patent Document 12). These compounds have both an RA system inhibiting activity and a PPARγ activation effect, and thus are expected to be used as an integrated agent for prevention and/or treatment of circulatory diseases (e.g., hypertension, heart disease, angina pectoris, cerebral vascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, kidney disease, and the like) or diabetes-related diseases (e.g., type 2 diabetes mellitus, diabetic complication, insulin resistant syndrome, metabolic syndrome, hyperinsulinemia, and the like) without increasing a risk of body fluid accumulation, body weight gain, peripheral edema, pulmonary edema, or congestive heart failure that are concerned over the use of TZD (Patent Document 1). Among them, for diabetic nephropathy, a synergistic prophylactic and/or therapeutic effect is expected from composite kidney protecting activity that is based on activities of RA system inhibition and PPARγ activation.
As a compound having the activities above, pyrimidine and triazine derivatives (Patent Document 1), imidazopyridine derivatives (Patent Document 2), indole derivatives (Patent Document 3), imidazole derivatives (Patent Document 4), and condensed ring derivatives (Patent Document 5) have been reported. However, there is no description or suggestion regarding the phenylpyridine derivatives of the present invention.
Meanwhile, Patent Document 6 discloses a compound represented by the following formula (A):

[in the formula, R1 is an optionally substituted hydrocarbon residue which is optionally bonded through a hetero atom, R2 is an optionally substituted 5 to 7 membered heterocyclic residue having, as a group capable of constituting the ring, a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom or a group convertible into them, X is a direct bond or bonding via a spacer having an atomic length of two or less between the ring Y and the ring W, W and Y are an optionally substituted aromatic hydrocarbon residue optionally containing a hetero atom or an optionally substituted heterocyclic residue; n is an integer of 1 or 2, a and b forming the heterocyclic residue are independently one or two optionally substituted carbon or hetero atoms, c is an optionally substituted carbon or hetero atom, and, in the group of the formula,

substituent groups on adjacent two atoms forming the ring are optionally bonded to each other to form a 5 to 6 membered ring together with the two atoms forming the ring]. As a preferred W—Y ring system, biphenyl is exemplified. In the Examples, only the biphenyl derivatives are specifically described. The compounds disclosed in Patent Document 6 are different from the compounds of the present invention in terms of the ring bonded to the pyridinyl methyl group. In addition, Patent Document 6 includes no descriptions or suggestions relating to a PPARγ activation effect as a pharmacological activity or treatment of diabetes, obesity, or metabolic syndromes.